Trace Amine-Associated Receptor 1 (TAAR1) is a Gs-coupled receptor that is a direct target of methamphetamine. It is co-localized in a subset of Substantia nigra dopamine neurons in both mouse and primate brain. Methamphetamine activation of TAAR1 is greatly enhanced by DAT, and TAAR1 activation results in altered DAT function as a consequence of cAMP elevation and phosphorylation. Accordingly, TAAR1 may play an important role in dopamine neuron function, and may be of particular importance to methamphetamine effects on the brain dopamine system. The focus of this grant is to determine the contribution of TAAR1 to the biological effects of methamphetamine, and whether the receptor is a plausible target for the development of novel therapeutics for methamphetamine addiction. The proposed studies utilize novel TAAR1 receptor knockout mice. There is no public information available on this mouse line;it has not been phenotyped, but is viable and confirmed to be transgenic. We will explore the role of TAAR1 in methamphetamine neurobiology at behavioral, cellular and gene expression levels in vitro and ex vivo using these mice to: 1) determine whether TAAR1 knockout mice have altered behavioral responses to methamphetamine, compared to their heterozygous and wild-type littermates;2) define a role for TAAR1 as a mediator of methamphetamine action on the dopamine transporter;and 3) explore whether TAAR1 influences methamphetamine-induced changes in gene expression in vivo, by comparing the pattern of methamphetamine-induced c-FOS expression in TAAR1 knockout mice vs. heterozygous and wild-type littermates and examining changes in the level of gene expression of both known and candidate genes that are affected by methamphetamine. We provide extensive preliminary data to support the hypothesis that methamphetamine action is mediated, in part, via TAAR1 and that methamphetamine response at TAAR1 is functionally interactive with DAT. Accordingly, we will explore the role of TAAR1 in methamphetamine neurobiology using a newly developed transgenic TAAR1 knockout mouse. TAAR1 is a Gs-linked receptor that is expressed in dopamine neurons and is a direct target of methamphetamine. Its recent discovery presents a significant new target for exploring the pharmacological action of methamphetamine in brain and for developing novel leads for therapeutic agents for treating methamphetamine addiction. This grant explores the role of TAAR1 in methamphetamine neurobiology at behavioral, cellular and gene expression levels in transgenic TAAR1 knockout mice.